BRCA2 mutations linked to worse outcomes, treatment responses in aggressive prostate cancer
Germline mutations in the BRCA2 gene have an adverse effect on metastatic castration-resistant prostate cancer outcomes that could be modified by the type of initial treatment used, according to results of a prospective, multicenter study published in Journal of Clinical Oncology.
“Our study shows that treatment and follow-up protocols used in patients with advanced prostate cancer may be inadequate for men with BRCA2 mutations,” David Olmos, MD, PhD, head of the prostate cancer clinical research unit at Spanish National Cancer Research Center, said in a press release. “We are currently studying the characteristics that make these tumors more aggressive and trying to establish new strategies to improve patient prognosis.”
The results are the first from the PROREPAIR-B study involving 38 Spanish hospitals and 419 men (median age at diagnosis, 66.2 years; range, 40.8-92.1) diagnosed with metastatic castration-resistant prostate cancer. Researchers screened the men for germline DNA damage repair mutations in 107 genes and followed the men for up to 5 years to assess the impact of mutations on disease progression and response to treatments.
The cohort included 68 mutation carriers, including 14 men with BRCA2 mutations, eight with ATM mutations and four with BRCA1 mutations. None of the patients had a PALB2 mutation.
The impact of ATM, BRCA1, BRCA2 and PALB2 germline mutations on cause-specific survival from diagnosis of metastatic castration-resistant prostate cancer served as the primary endpoint.
Secondary endpoints included the link between germline DNA damage repair gene subgroups and responses to treatments and combined PFS from first systemic therapy to progression on the second systemic therapy (PFS2).
The study failed to meet its primary endpoint, as results showed no statistically significant difference in cause-specific survival between ATM, BRCA1, BRCA2 and PALB2 carriers and noncarriers (23.3 months vs. 33.2 months).
However, germline BRCA2 carriers had significantly shorter cause-specific survival than noncarriers (17.4 months vs. 33.2 months; P = .027), leading researchers to identify germline BRCA2 mutations as an independent prognostic factor for poor cause-specific survival (HR = 2.11; 95% CI, 1.06 to 4.18).
Researchers also found significant interactions between germline BRCA2 status and treatment with androgen signaling inhibitors vs. taxane therapy (adjusted cause-specific survival, P = .014; adjusted PFS2, P = .005).
Germline BRCA2 carriers who received first-line abiraterone or enzalutamide (Xtandi, Astellas) vs. taxanes had longer cause-specific survival (24 months vs. 17 months) and PFS2 (18.9 months vs. 8.6 months).
Researchers noted that additional screening of large groups of patients with different genetic backgrounds is needed to help establish the frequency of the inherited gene mutations.
“This is the first prospective study... that shows BRCA2 mutations themselves, regardless of other factors, are responsible for poor prognosis and can have an impact on treatment responses,” lead study author Elena Castro, MD, PhD, of the prostate cancer clinical research unit at Spanish National Cancer Research Center, said in a press release. “It should be noted that we identified germline mutations, although in a number of patients there were no familial cancer cases that might have indicated the presence of such genetic alterations. These mutations should be identified in patients with metastatic prostate cancer, since detecting such alterations is important for the diagnosis and management of the disease and for the patients’ families, whose risk of developing breast, ovarian and pancreatic cancer is increased.”– by John DeRosier
Disclosures: The CRIS Cancer Foundation; Health Institute Carlos III; Prostate Cancer Foundation; Spanish Association Against Cancer; Spanish Ministry of Education, Culture and Sports; and Spanish Ministry of Science, Innovation and Universities funded this study. Olmos reports honoraria from Bayer, Janssen and Sanofi; consultant/advisory roles with AstraZeneca, Bayer, Clovis Oncology and Janssen; institutional research funding from Astellas/Medivation, AstraZeneca, Bayer, Genentech, Janssen, Pfizer, Roche and Tokai Pharmaceuticals; and travel accommodations and expenses from Bayer, Ipsen and Janssen. Castro reports honoraria from Astellas Pharma, AstraZeneca, Bayer and Janssen-Cilag; consultant/advisory roles with Bayer and Janssen; institutional research funding from AstraZeneca, Bayer and Janssen; and travel expenses from Astellas Pharma, Bayer, Janssen and Roche. Please see the study for all other authors’ relevant financial disclosures.